Horace Loh - Academia.edu (original) (raw)

Papers by Horace Loh

Research paper thumbnail of Roles of .MU.-OPIOID Receptors in Development of Tolerance to Diisopropylfluorophosphate (DFP)

Journal of Toxicological Sciences, 2005

Research paper thumbnail of Beta‐arrestin 1 and beta‐arrestin 2 differentially direct the phosphorylation‐dependent and ‐independent internalization and desensitization of delta‐opioid receptor

Research paper thumbnail of Impaired water maze learning performance in �-opioid receptor knockout mice

Research paper thumbnail of Influence of morphine on protein synthesis in discrete subcellular fractions of the rat brain

Research communications in chemical pathology and pharmacology, 1976

Extensive time course (15 min to 24 hr) measurements were made of the effects of acute and chroni... more Extensive time course (15 min to 24 hr) measurements were made of the effects of acute and chronic morphine treatment on the incorporation of 3H-lysine into rat brain proteins. Acute and chronic morphine treatment inhibited cortical protein synthesis in the microsomal (Mc), mitochondrial (Mw) and soluble fractions (Sol.). In the subcortex, acute morphine stimulated labelled protein accumulation in the Mc and Mw fractions, Chronic morphine treatment decreased 3H-lys-protein accumulation in these fractions.

Research paper thumbnail of Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling

Nucleic Acids Research, 2014

Research paper thumbnail of Novel function of the poly(C)-binding protein  CP3 as a transcriptional repressor of the mu opioid receptor gene

The FASEB Journal, 2007

The alpha-complex proteins (␣CP) are generally known as RNA-binding proteins that interact in a s... more The alpha-complex proteins (␣CP) are generally known as RNA-binding proteins that interact in a sequence-specific fashion with single-stranded poly(C). These proteins are mainly involved in various post-transcriptional regulations (e.g., mRNA stabilization or translational activation/silencing). Here we report a novel function of ␣CP3, a member of the ␣CP family. ␣CP3 bound to the double-stranded poly(C) element essential for the mu opioid receptor (MOR) promoter and repressed the promoter activity at the transcriptional level. We identified ␣CP3 using affinity column chromatography containing the doublestranded poly(C) element and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. ␣CP3 binding to the poly(C) sequence of the MOR gene was sequence specific, as confirmed by the supershift assay. In cotransfection studies, ␣CP3 repressed the MOR promoter only when the poly(C) sequence was intact. Ectopic expression of ␣CP3 led to repression of the endogenous MOR transcripts in NS20Y cells. When ␣CP3 was disrupted using small interfering RNA (siRNA) in NS20Y cells, the transcription of the endogenous target MOR gene was increased significantly. Our data suggest that ␣CP3 can function as a repressor of MOR transcription dependent on the MOR poly(C) sequence. We demonstrate for the first time a role of ␣CP3 as a transcriptional repressor in MOR gene regulation.

Research paper thumbnail of Endorphins may function in heat adaptation

Proceedings of the National Academy of Sciences, 1978

Administration of the opiate antagonist naloxone to rats after acute or chronic heat exposure pre... more Administration of the opiate antagonist naloxone to rats after acute or chronic heat exposure precipitates an increase in colonic temperature, an increase in escape attempts, and a decrease in body weight. These changes are accompanied by signs associated with hyperthermia such as salivation, diarrhea, and an abnormal extended posture. Although brain endorphin involvement is possible, hypophysectomy diminishes the intensity and magnitude of these naloxone effects, indicating that the naloxone effect in intact animals may be due to a functional antagonism of pituitary endorphins. These observations suggest that endorphins attenuate physiological responses to thermal and noxious stimuli triggered in common neuroanatomical pathways by heat.

Research paper thumbnail of β-Endorphin as a potent analgesic by intravenous injection

Research paper thumbnail of Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene

Journal of Biomedical Science, 2010

Background Opioid analgesics such as morphine and meperidine have been used to control moderate t... more Background Opioid analgesics such as morphine and meperidine have been used to control moderate to severe pain for many years. However, these opioids have many side effects, including the development of tolerance and dependence after long-term use, which has limited their clinical use. We previously reported that mutations in the mu-opioid receptors (MOR) S196L and S196A rendered them responsive to the opioid antagonist naloxone without altering the agonist phenotype. In MORS196A knock-in mice, naloxone and naltrexone were antinociceptive but did not cause tolerance or physical dependence. In this study we delivery this mutated MOR gene into pain related pathway to confirm the possibility of in vivo transfecting MORS196A gene and using naloxone as a new analgesic agent. Methods The MOR-knockout (MOR-KO) mice were used to investigate whether morphine and naloxone could show antinociceptive effects when MORS196A gene was transfected into the spinal cords of MOR-KO mice. Double-strande...

Research paper thumbnail of An Intronic Ikaros-binding Element Mediates Retinoic Acid Suppression of the Kappa Opioid Receptor Gene, Accompanied by Histone Deacetylation on the Promoters

Journal of Biological Chemistry, 2001

The mouse kappa opioid receptor (KOR) gene is constitutively expressed in mouse embryonal carcino... more The mouse kappa opioid receptor (KOR) gene is constitutively expressed in mouse embryonal carcinoma P19 stem cells and suppressed by retinoic acid (RA) in cells undergoing neuronal differentiation. A negative regulatory element is located within intron 1 of the KOR gene, which contains an Ikaros (Ik)-binding site (GG-GAAgGGGAT). This sequence is an Ik-1 respondive, functionally negative element as demonstrated in the context of both natural KOR and heterologous promoters. The two underlined G residues of the second halfsite are critical for Ik-1 binding and Ik-mediated repression of the KOR gene. RA induces Ik-1 expression within 1 day of treatment and suppresses KOR expression between 2 and 3 days. Overexpression of Ik-1 in P19 suppresses endogenous KOR gene expression, accompanied by increased binding of Ik-1 to the Ik-binding site and chromatin histone deacetylation on KOR promoters. It is proposed that in an RA-induced P19 differentiation model, RA elevates Ik-1 expression, which recruits histone deacetylase to intron 1 of the KOR gene and silences KOR gene promoters.

Research paper thumbnail of Possible physiological control of morphine analgesia in mice

European Journal of Pharmacology, 1982

Several laboratories have reported that dynorphin and vasopressin may be present in the same neur... more Several laboratories have reported that dynorphin and vasopressin may be present in the same neurons and released together in a fixed ratio. In this study, we report that vasopressin and dynorphin can regulate morphine-induced analgesia in the mouse tail-flick test. Its action is opposite that observed for dynorphin because, when administered simultaneously with morphine, vasopressin in a dose-related manner potentiated morphine-induced analgesia while dynorphin antagonized it. When vasopressin and dynorphin is administered together with morphine, morphine EDso returned to control level.

Research paper thumbnail of Apparent protein kinase activity in oligodendroglial chromatin after chronic morphine treatment

Biochemical Pharmacology, 1976

Abstract The oligodendroglial nuclei were purified from mouse brain with more than 97 per cent ho... more Abstract The oligodendroglial nuclei were purified from mouse brain with more than 97 per cent homogeneity. Cyclic AMP-independent phosphorylation of non-histone protein in oligodendroglial chromatin was studied. Morphine sulfate, in vitro, had no effect on phosphorylation. However, chronic morphine treatment resulted in an increase of phosphorylation in high molecular weight regions of sodium dodecylsulfate (SDS) electrophoresis gel. The increase was not the result of a decrease in phosphoprotein phosphatase activity.

Research paper thumbnail of Effects of chronic administration of morphine on pentobarbital responses in the mouse

Biochemical Pharmacology, 1976

Research paper thumbnail of Reduced nNOS expression induced by repeated nicotine treatment in μ-opioid receptor knockout mice

Neuroscience Letters, 2005

To determine whether neuronal nitric oxide synthase (nNOS) is involved in nicotine-induced behavi... more To determine whether neuronal nitric oxide synthase (nNOS) is involved in nicotine-induced behavioral sensitization in-opioid receptor knockout mice we adopted an immunohistochemical approach. Our results confirm that repeated nicotine administration increased locomotor activity in wild-type mice, but failed to increase locomotor activity in-opioid receptor knockout mice, thus suggesting that the-opioid receptor is involved in behavioral sensitization. Higher numbers of nNOS-positive cells were observed in the striatum of wild-type mice repeatedly treated with nicotine than in saline-treated wild-type mice. However,-opioid receptor knockout mice showed significantly lower nicotine-induced nNOS expression in the striatum versus wild-type mice. No differences were found in the hilus of the dentate gyrus between wild-type and-opioid receptor knockout mice. These findings demonstrate that the absence of-opioid receptors can cause a significant reduction in the expression of nNOS in the striatum, as induced by repeated nicotine treatment.

Research paper thumbnail of Mu and delta receptors mediate morphine effects on phagocytosis by murine peritoneal macrophages

Journal of Neuroimmunology, Mar 31, 2003

Studies with selective opioid agonists show that mu- and delta(2)-opioid receptors, but not kappa... more Studies with selective opioid agonists show that mu- and delta(2)-opioid receptors, but not kappa, are involved in opioid inhibition of phagocytosis in elicited murine macrophages. All mu and delta(2) agonists tested had similar maximal effects on phagocytosis, and all dose-response curves suggest positive cooperativity. In addition, mu and delta antagonists antagonized the effect of both mu and delta agonists. Furthermore, in mu-opioid receptor knockout mice (MORKO), we observed a decrease in potency and maximal effect for a delta agonist. These data suggest that mu and delta receptors are not only involved in the modulation of phagocytosis in macrophages, but they also affect each other's activity by an unknown cooperative mechanism.

Research paper thumbnail of Increased dopamine D2 receptor binding and enhanced apomorphine-induced locomotor activity in μ-opioid receptor knockout mice

Previous studies from our laboratory have indicated possible interactions between opioidergic and... more Previous studies from our laboratory have indicated possible interactions between opioidergic and dopaminergic neurons in the central nervous system. In this study, apomorphine-induced locomotor activity and the D1 and D2 subtype dopamine receptor binding were examined in mice lacking the mu-opioid receptor genes. The ambulatory time, vertical time and total motor distance of locomotor activity were measured after administration of apomorphine (2mg/kg, i.p.) for a period of 90min. The autoradiographic studies of D1 and D2 dopamine receptors were conducted using [3H] SCH23390 and [3H] raclopride as ligand, respectively. In wild type mice that received apomorphine, 2mg/kg, i.p., the locomotor activity such as ambulatory time, vertical time and total motor distance were not significantly altered as compared with that of the saline control group. However, the locomotor activity measured was significantly increased in the same dose of apomorphine treated mu-opioid receptor knockout mice between 5 and 40min after administration. The results obtained also show that the binding of D2 dopamine receptor in mu-opioid receptor knockout mice was significantly higher than that of the wild type in the caudate putamen. However, the binding of the D1 dopamine receptor in mu-opioid receptor knockout mice was not significantly different from that of the wild type. It appears that the apomorphine treated mu-opioid receptor knockout mice showed enhancement in locomotor activity. The enhanced locomotor activity may be related to the compensatory up-regulation of D2 dopamine receptors in mice lacking mu-opioid receptor genes.

Research paper thumbnail of Roles of .MU.-OPIOID Receptors in Development of Tolerance to Diisopropylfluorophosphate (DFP)

Journal of Toxicological Sciences, 2005

Research paper thumbnail of Beta‐arrestin 1 and beta‐arrestin 2 differentially direct the phosphorylation‐dependent and ‐independent internalization and desensitization of delta‐opioid receptor

Research paper thumbnail of Impaired water maze learning performance in �-opioid receptor knockout mice

Research paper thumbnail of Influence of morphine on protein synthesis in discrete subcellular fractions of the rat brain

Research communications in chemical pathology and pharmacology, 1976

Extensive time course (15 min to 24 hr) measurements were made of the effects of acute and chroni... more Extensive time course (15 min to 24 hr) measurements were made of the effects of acute and chronic morphine treatment on the incorporation of 3H-lysine into rat brain proteins. Acute and chronic morphine treatment inhibited cortical protein synthesis in the microsomal (Mc), mitochondrial (Mw) and soluble fractions (Sol.). In the subcortex, acute morphine stimulated labelled protein accumulation in the Mc and Mw fractions, Chronic morphine treatment decreased 3H-lys-protein accumulation in these fractions.

Research paper thumbnail of Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling

Nucleic Acids Research, 2014

Research paper thumbnail of Novel function of the poly(C)-binding protein  CP3 as a transcriptional repressor of the mu opioid receptor gene

The FASEB Journal, 2007

The alpha-complex proteins (␣CP) are generally known as RNA-binding proteins that interact in a s... more The alpha-complex proteins (␣CP) are generally known as RNA-binding proteins that interact in a sequence-specific fashion with single-stranded poly(C). These proteins are mainly involved in various post-transcriptional regulations (e.g., mRNA stabilization or translational activation/silencing). Here we report a novel function of ␣CP3, a member of the ␣CP family. ␣CP3 bound to the double-stranded poly(C) element essential for the mu opioid receptor (MOR) promoter and repressed the promoter activity at the transcriptional level. We identified ␣CP3 using affinity column chromatography containing the doublestranded poly(C) element and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. ␣CP3 binding to the poly(C) sequence of the MOR gene was sequence specific, as confirmed by the supershift assay. In cotransfection studies, ␣CP3 repressed the MOR promoter only when the poly(C) sequence was intact. Ectopic expression of ␣CP3 led to repression of the endogenous MOR transcripts in NS20Y cells. When ␣CP3 was disrupted using small interfering RNA (siRNA) in NS20Y cells, the transcription of the endogenous target MOR gene was increased significantly. Our data suggest that ␣CP3 can function as a repressor of MOR transcription dependent on the MOR poly(C) sequence. We demonstrate for the first time a role of ␣CP3 as a transcriptional repressor in MOR gene regulation.

Research paper thumbnail of Endorphins may function in heat adaptation

Proceedings of the National Academy of Sciences, 1978

Administration of the opiate antagonist naloxone to rats after acute or chronic heat exposure pre... more Administration of the opiate antagonist naloxone to rats after acute or chronic heat exposure precipitates an increase in colonic temperature, an increase in escape attempts, and a decrease in body weight. These changes are accompanied by signs associated with hyperthermia such as salivation, diarrhea, and an abnormal extended posture. Although brain endorphin involvement is possible, hypophysectomy diminishes the intensity and magnitude of these naloxone effects, indicating that the naloxone effect in intact animals may be due to a functional antagonism of pituitary endorphins. These observations suggest that endorphins attenuate physiological responses to thermal and noxious stimuli triggered in common neuroanatomical pathways by heat.

Research paper thumbnail of β-Endorphin as a potent analgesic by intravenous injection

Research paper thumbnail of Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene

Journal of Biomedical Science, 2010

Background Opioid analgesics such as morphine and meperidine have been used to control moderate t... more Background Opioid analgesics such as morphine and meperidine have been used to control moderate to severe pain for many years. However, these opioids have many side effects, including the development of tolerance and dependence after long-term use, which has limited their clinical use. We previously reported that mutations in the mu-opioid receptors (MOR) S196L and S196A rendered them responsive to the opioid antagonist naloxone without altering the agonist phenotype. In MORS196A knock-in mice, naloxone and naltrexone were antinociceptive but did not cause tolerance or physical dependence. In this study we delivery this mutated MOR gene into pain related pathway to confirm the possibility of in vivo transfecting MORS196A gene and using naloxone as a new analgesic agent. Methods The MOR-knockout (MOR-KO) mice were used to investigate whether morphine and naloxone could show antinociceptive effects when MORS196A gene was transfected into the spinal cords of MOR-KO mice. Double-strande...

Research paper thumbnail of An Intronic Ikaros-binding Element Mediates Retinoic Acid Suppression of the Kappa Opioid Receptor Gene, Accompanied by Histone Deacetylation on the Promoters

Journal of Biological Chemistry, 2001

The mouse kappa opioid receptor (KOR) gene is constitutively expressed in mouse embryonal carcino... more The mouse kappa opioid receptor (KOR) gene is constitutively expressed in mouse embryonal carcinoma P19 stem cells and suppressed by retinoic acid (RA) in cells undergoing neuronal differentiation. A negative regulatory element is located within intron 1 of the KOR gene, which contains an Ikaros (Ik)-binding site (GG-GAAgGGGAT). This sequence is an Ik-1 respondive, functionally negative element as demonstrated in the context of both natural KOR and heterologous promoters. The two underlined G residues of the second halfsite are critical for Ik-1 binding and Ik-mediated repression of the KOR gene. RA induces Ik-1 expression within 1 day of treatment and suppresses KOR expression between 2 and 3 days. Overexpression of Ik-1 in P19 suppresses endogenous KOR gene expression, accompanied by increased binding of Ik-1 to the Ik-binding site and chromatin histone deacetylation on KOR promoters. It is proposed that in an RA-induced P19 differentiation model, RA elevates Ik-1 expression, which recruits histone deacetylase to intron 1 of the KOR gene and silences KOR gene promoters.

Research paper thumbnail of Possible physiological control of morphine analgesia in mice

European Journal of Pharmacology, 1982

Several laboratories have reported that dynorphin and vasopressin may be present in the same neur... more Several laboratories have reported that dynorphin and vasopressin may be present in the same neurons and released together in a fixed ratio. In this study, we report that vasopressin and dynorphin can regulate morphine-induced analgesia in the mouse tail-flick test. Its action is opposite that observed for dynorphin because, when administered simultaneously with morphine, vasopressin in a dose-related manner potentiated morphine-induced analgesia while dynorphin antagonized it. When vasopressin and dynorphin is administered together with morphine, morphine EDso returned to control level.

Research paper thumbnail of Apparent protein kinase activity in oligodendroglial chromatin after chronic morphine treatment

Biochemical Pharmacology, 1976

Abstract The oligodendroglial nuclei were purified from mouse brain with more than 97 per cent ho... more Abstract The oligodendroglial nuclei were purified from mouse brain with more than 97 per cent homogeneity. Cyclic AMP-independent phosphorylation of non-histone protein in oligodendroglial chromatin was studied. Morphine sulfate, in vitro, had no effect on phosphorylation. However, chronic morphine treatment resulted in an increase of phosphorylation in high molecular weight regions of sodium dodecylsulfate (SDS) electrophoresis gel. The increase was not the result of a decrease in phosphoprotein phosphatase activity.

Research paper thumbnail of Effects of chronic administration of morphine on pentobarbital responses in the mouse

Biochemical Pharmacology, 1976

Research paper thumbnail of Reduced nNOS expression induced by repeated nicotine treatment in μ-opioid receptor knockout mice

Neuroscience Letters, 2005

To determine whether neuronal nitric oxide synthase (nNOS) is involved in nicotine-induced behavi... more To determine whether neuronal nitric oxide synthase (nNOS) is involved in nicotine-induced behavioral sensitization in-opioid receptor knockout mice we adopted an immunohistochemical approach. Our results confirm that repeated nicotine administration increased locomotor activity in wild-type mice, but failed to increase locomotor activity in-opioid receptor knockout mice, thus suggesting that the-opioid receptor is involved in behavioral sensitization. Higher numbers of nNOS-positive cells were observed in the striatum of wild-type mice repeatedly treated with nicotine than in saline-treated wild-type mice. However,-opioid receptor knockout mice showed significantly lower nicotine-induced nNOS expression in the striatum versus wild-type mice. No differences were found in the hilus of the dentate gyrus between wild-type and-opioid receptor knockout mice. These findings demonstrate that the absence of-opioid receptors can cause a significant reduction in the expression of nNOS in the striatum, as induced by repeated nicotine treatment.

Research paper thumbnail of Mu and delta receptors mediate morphine effects on phagocytosis by murine peritoneal macrophages

Journal of Neuroimmunology, Mar 31, 2003

Studies with selective opioid agonists show that mu- and delta(2)-opioid receptors, but not kappa... more Studies with selective opioid agonists show that mu- and delta(2)-opioid receptors, but not kappa, are involved in opioid inhibition of phagocytosis in elicited murine macrophages. All mu and delta(2) agonists tested had similar maximal effects on phagocytosis, and all dose-response curves suggest positive cooperativity. In addition, mu and delta antagonists antagonized the effect of both mu and delta agonists. Furthermore, in mu-opioid receptor knockout mice (MORKO), we observed a decrease in potency and maximal effect for a delta agonist. These data suggest that mu and delta receptors are not only involved in the modulation of phagocytosis in macrophages, but they also affect each other's activity by an unknown cooperative mechanism.

Research paper thumbnail of Increased dopamine D2 receptor binding and enhanced apomorphine-induced locomotor activity in μ-opioid receptor knockout mice

Previous studies from our laboratory have indicated possible interactions between opioidergic and... more Previous studies from our laboratory have indicated possible interactions between opioidergic and dopaminergic neurons in the central nervous system. In this study, apomorphine-induced locomotor activity and the D1 and D2 subtype dopamine receptor binding were examined in mice lacking the mu-opioid receptor genes. The ambulatory time, vertical time and total motor distance of locomotor activity were measured after administration of apomorphine (2mg/kg, i.p.) for a period of 90min. The autoradiographic studies of D1 and D2 dopamine receptors were conducted using [3H] SCH23390 and [3H] raclopride as ligand, respectively. In wild type mice that received apomorphine, 2mg/kg, i.p., the locomotor activity such as ambulatory time, vertical time and total motor distance were not significantly altered as compared with that of the saline control group. However, the locomotor activity measured was significantly increased in the same dose of apomorphine treated mu-opioid receptor knockout mice between 5 and 40min after administration. The results obtained also show that the binding of D2 dopamine receptor in mu-opioid receptor knockout mice was significantly higher than that of the wild type in the caudate putamen. However, the binding of the D1 dopamine receptor in mu-opioid receptor knockout mice was not significantly different from that of the wild type. It appears that the apomorphine treated mu-opioid receptor knockout mice showed enhancement in locomotor activity. The enhanced locomotor activity may be related to the compensatory up-regulation of D2 dopamine receptors in mice lacking mu-opioid receptor genes.